Helmut Buschmann

• RWTH Aachen University

Small-molecule capsid assembly modulators (CAMs) have been recently recognized as promising antiviral agents for curing chronic hepatitis B virus (HBV) infection. A target-based in silico screening study is described, aimed towards the discovery of novel HBV CAMs. Initial optimization of four weakly active screening hits was performed via focused l...

The long-term stability of an active-pharmaceutical ingredient and its drug products plays an important role in the licensing process of new pharmaceuticals and for the application of the drug at the patient. It is, however, difficult to predict degradation profiles at early stages of the development of new drugs, making the entire process very tim...

When the nucleoside analogue acyclovir was introduced in the early 1980s, it presented a game-changing treatment modality for herpes simplex virus infections. Since then, work has been ongoing to improve the weaknesses that have now been identified: a narrow time window for therapeutic success, resistance in immunocompromised patients, little influ...

Forced oxidative mechanochemical degradation of clopidogrel hydrogensulfate as a model compound leads to selective formation of degradants in less than 15 minutes.

Pritelivir (AIC316, BAY 57-1293) was discovered as a highly potent drug against herpes simplex viruses with a novel mode of action, i.e. inhibition of the viral helicase-primase. A side...

In the development of new pharmaceutical formulations it is important to consider the possible interactions between the active pharmaceutical ingredient (API) and excipients which is a well-known problem. The objective of the work presented here was to investigate such reactions by means of diffusion ordered NMR spectroscopy (DOSY). The known react...

The book provides a current overview and comprehensive compilation for medicinal chemists that discusses the effects of aiming for multiple targets on the entire drug development process. The result is a broad survey of current and future strategies for drug selectivity in medicinal chemistry with theoretical but also practical aspects. Different s...

A series of congeners structurally related to pritelivir, N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl) phenyl]acetamide, a helicase-primase inhibitor for the treatment of herpes simplex virus infections, was prepared. The synthesized primary and secondary sulfonamides were investigated as inhibitors of six physiologic...

The selective optimization of side activities (SOSA) approach uses old drugs for new pharmacological targets. The aim is to screen only a limited number of drug molecules that are structurally and therapeutically diverse and have known safety and bioavailability in humans. The SOSA approach appears to be an efficient strategy for drug discovery, pa...

Pain is the most common reason for patients seeking medical care resulting in an estimated world market for analgesics of more than USD 50 billion. Pain is a highly complex, heterogeneous and dynamic process characterized by specific patterns of phenotypic sensory neuronal change. Current treatment options for pain include opioids and non-opioid an...

Novel antiviral drugs, which are less prone to resistance development, are desirable alternatives to the currently approved drugs for the treatment of potentially serious influenza virus infections. The viral polymerase is highly conserved and serves as an attractive target for antiviral drugs since potent inhibitors would directly stop viral repli...

The present invention relates to a compound having the general formula (II), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Furthermore, specifi...

Forced degradation studies trigger decomposition of drug substance and drug product at conditions more severe than accelerated conditions to attain a profound understanding of its stability and degradation, and have become an essential step in the design of a regulatory compliant stability program. However, since stress-testing conditions may vary...

The present invention relates to a compound having the general formula (Di), (Dii), or (Diii), optionally in the form of a pharmaceutically acceptable salt, solvate, polymorph, codrug, cocrystal, prodrug, tautomer, racemate, enantiomer, or diastereomer or mixture thereof, which are useful in treating, ameloriating or preventing a viral disease. Fur...

The present invention relates to a process for the preparation of (1R,2R)-3-dimethylamino-1-ethyl-2-methyl-propyl)-phenol.

Compounds of the formula II can be hydrogenated to the corresponding butane derivatives in the presence of homogeneous cataslysts composed of metal salts or complexes containing metals selected from the group consisting of Rh, Ir, and Ru and preferably containing diphosphine ligands, with, in addition, excellent optical yields being achieved when...

A process for the preparation of substituted 3-(1-amino-2-methylpentane-3-yl)phenyl compounds which has advantages over conventional processes with respect to higher conversions and yields, flexibility, a shorter overall route, environmentally acceptable conditions, influence of stereoselectivity such as diastereoselectivity in a targeted manner an...

Substituted 1-oxa-2,8-diaza-spiro[4,5]dec-2-ene compounds and processes for their production, the use thereof for producing pharmaceutical compositions, pharmaceutical compositions containing these compounds and methods of treatment using these compounds.

While opioids are potent analgesics widely used in the management of pain, a number of well-known adverse effects limit their use. The sigma-1 receptor is a ligand-regulated molecular chaperone involved in pain processing, including modulation of opioid antinociception. However, data supporting the potential use of sigma-1 receptor ligands as suita...

From insects to cancer: N-Cyano sulfoximines were evaluated for COX inhibition and antiproliferative activity against a panel of cancer cell lines. The most active compound exhibited potent COX-2 inhibition, some selectivity for COX-2 over COX-1, only slight cytotoxicity towards healthy cells (HaCaT skin cells), and no mutagenic potential (as deter...

The addition of halides to the cationic solvate complexes of the type [Rh(PP)(solvent)2][anion] leads to the formation of trinuclear μ3-halide-bridged complexes. The corresponding complexes [Rh3(PP)3(μ3-X)2][BF4] with X = Cl or Br and diphosphines PP Me-DuPHOS, Et-DuPHOS, DIPAMP, t-Bu-BisP* and Tangphos were characterized – in most cases – also by...

List of Abbreviations Introduction The Discovery of Tapentadol The Preclinical and Clinical Profile of Tapentadol Summary References

Sulfoximine- and sulfilimine-based diamino-diphenyl sulfone (DAPSON) analogues have been prepared and their COX- 1 and COX-2 inhibition potencies as well as LTB4 and TNF binding properties were studied. Furthermore, their antiproliferative activities on cancer cell growth were investigated. Neither compounds showed significant bioactivities

The synthesis and pharmacological activity of a new series of 1-arylpyrazoles as potent σ(1) receptor (σ(1)R) antagonists are reported. The new compounds were evaluated in vitro in human σ(1)R and guinea pig σ(2) receptor (σ(2)R) binding assays. The nature of the pyrazole substituents was crucial for activity, and a basic amine was shown to be nece...

Introduction: Many opioid analgesics share common structural elements; however, minor differences in structure can result in major differences in pharmacological activity, pharmacokinetic profile, and clinical efficacy and tolerability. Areas covered: This review compares and contrasts the chemistry, pharmacodynamics, pharmacokinetics, and CNS '...

Sulfoximine-based acyclic triaryl olefins 8 and 9 have been prepared and initial studies have been performed to determine their biological profiles. In contrast to their sulfonyl-substituted analog 2 sulfoximines 8 and 9 show low COX inhibitory activity. All compounds affect the estrogen receptors. While sulfone 2 interacts exclusively with ER β, s...

Two series of σ(1) ligands with a spiro[[2]benzopyran-1,3'-pyrrolidine] (3) and a spiro[[2]benzofuran-1,3'-pyrrolidine] (4) framework were synthesized and pharmacologically evaluated. Several reaction steps were considerably improved by microwave irradiation. The σ(1) affinity of the spirocyclic ligands correlates nicely with the benzene-N-distance...

On the basis of the 6',7'-dihydrospiro[piperidine-4,4'-thieno[3,2-c]pyran] framework, a series of more than 30 σ ligands with versatile substituents in 1-, 2'-, and 6'-position has been synthesized and pharmacologically evaluated in order to find novel structure-affinity relationships. It was found that a cyclohexylmethyl residue at the piperidine...

Sulfoximines (VIII) and (X) are prepared by combining the original strategy for the synthesis of Vioxx® with the chemistry developed by the authors.

Paracetamol is one of the most popular and widely used drugs for the treatment of pain and fever and provides safe and effective relief of these symptoms since decades. The mechanism of action is very complex and involves the inhibition of the peroxidase portion of the cyclooxygenase enzyme together with the modulation of the serotoninergic and can...

The article contains sections titled: 1.Opioids1.1.Opioids in Clinical Use1.1.1.Morphine and Morphinane Derivatives1.1.2.Piperidine Derivatives1.1.3.Fentanyl and Congeners1.1.4.Methadone and Congeners1.2.Other Structures1.2.1.Mixed Opioid Agonist-Antagonists and Partial Agonists1.2.2.Opioid Antagonists2.Anti-Neuropathic Analgesics and Other Nonopio...

The article contains sections titled: 1.Introduction2.Salicylates3.Para-Aminophenol Derivatives4.Anthranilates5.Arylacetic Acids6.Arylpropionic Acids7.Pyrazolinone Derivatives8.Acidic Enolic Compounds8.1.Pyrazolidine-3,5-diones8.2.Arylsulfonamides (Oxicames)9.Other Structures10.COX-2 Inhibitors10.1.Nonselective COXC-2 Inhibitors10.2.Selective COX-2...

The novel class of spirocyclic σ(1) ligands 3 (6',7'-dihydro-1'H-spiro[piperidine-4,4'-pyrano[4,3-c]pyrazoles]) was designed by the combination of the potent σ(1) ligands 1 and 2 in one molecule. Thorough structure affinity relationships were derived by the variation of the substituents in position 1', 1, and 6'. Whereas the small electron rich met...

The syntheses and biological profiles of sulfoximine-based Vioxx analogs 2 are described. Interesting data have been obtained for 2a, which shows a selective COX-2 inhibition (albeit not as strong as Vioxx itself) exhibiting reduced hERG activity compare to the parent sulfone Vioxx (1).

Based on the pharmacophore model of Glennon the conformationally restricted σ(1) receptor ligand 2 with a 1,3-dioxane moiety has been designed and synthesized. The three step synthesis (transacetalization with pentane-1,3,5-triol, tosylation, and nucleophilic substitution with benzylamine) provided diastereoselectively the cis-configured 1,3-dioxan...

Paracetamol ist eines der bekanntesten und meistverbreiteten Arzneimittel. Seit vielen Jahrzehnten wird es zur Fiebersenkung und gegen leichte bis mittelstarke Schmerzen eingesetzt und ist dabei zuverlässig wirksam und gut verträglich. Der Wirkmechanismus ist sehr komplex und beruht auf dem Zusammenspiel mehrerer Komponenten: einer Hemmung der Cycl...

For Abstract see ChemInform Abstract in Full Text.

The efficient design of stereochemically challenging ring systems by ring opening of heterobicyclic alkenes has become a very important reaction in the chemistry of CC and CX bond formation. By using the hitherto applied in situ technique for the generation of the μ2-bridged, dimeric neutral rhodium complexes, however, the catalytically active spec...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Anti-inflammatory efficacy of non-steroidal anti-inflammatory drugs (NSAIDs) has been related to their properties as inhibitors of cyclooxygenase (COX)-mediated prostaglandin (PG) synthesis. However, recent studies have suggested that variations of the in vivo anti-inflammatory actions among different NSAIDs could not be solely explained by COX inh...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 100 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

Objectives The pharmacology and metabolism of the potent σ1 receptor ligand 1′-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4′-piperidine] were evaluated. Methods The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin...

The present invention relates to co-crystals of duloxetine and co-crystal formers selected from COX-INHIBITORs, processes for preparation of the same and their uses as medicaments or in pharmaceutical formulations, more particularly for the treatment of pain. Specific COX-INHIBITORS are naproxen and tolmetin.

Several voltage-gated sodium channels are expressed in primary sensory neurons where they control excitability and participate in the generation and propagation of action potentials. Peripheral nerve injury-induced alterations in both tetrodotoxin (TTX)-sensitive and TTX-resistant sodium channels have been proposed to contribute to neuropathic pain...

The symmetrically connected spiro[[2]benzopyran-1,4'-piperidines] 1 are highly potent and selective sigma(1) receptor ligands. Changing the position of the spirocyclic nitrogen atom led to the unsymmetrically connected spiro[[2]benzopyran-1,3'-piperidines] 2 with a reduced distance between the aromatic system and the basic nitrogen atom. The synthe...

The pharmacology and metabolism of the potent sigma1 receptor ligand 1'-benzyl-3-methoxy-3H-spiro[[2]benzofuran-1,4'-piperidine] were evaluated. The compound was tested against a wide range of receptors, ion channels and neurotransmitter transporters in radioligand binding assays. Analgesic activity was evaluated using the capsaicin pain model. Met...

This work aimed to evaluate the potential role of the 5-HT(7) receptor in nociception secondary to a sensitizing stimulus in mice. For this purpose, the effects of relevant ligands (5-HT(7) receptor agonists: AS-19, MSD-5a, E-55888; 5-HT(7) receptor antagonists: SB-258719, SB-269970; 5-HT(1A) receptor agonist: F-13640; 5-HT(1A) receptor antagonist:...

ChemInform is a weekly Abstracting Service, delivering concise information at a glance that was extracted from about 200 leading journals. To access a ChemInform Abstract of an article which was published elsewhere, please select a “Full Text” option. The original article is trackable via the “References” option.

The synthesis of novel tricyclic 1,2,3-triazoles starting from cyclic epoxides via the sequential azidolysis, propargylation and 1,3-dipolar cycloaddition is described. Derivatization by N-arylation reaction and the synthesis of enantiomerically pure compounds is also reported. Some of these compounds exhibit significant affinity for the sigma-1 re...

A straightforward synthesis of (S)-pregabalin in 28% overall yield starting from d-mannitol acetonide, as a primary source of chirality, is presented. The process is suitable for large-scale synthesis and involves simple and high-yielding chemical transformations as well as low-cost commercially available reagents.

The increasing global prevalence of obesity unequivocally demonstrates that neither behavioural (diet and exercise) nor pharmacological approaches to this health problem are working. In this area of high unmet clinical need, the 5-HT6 receptor has generated enormous interest amongst academic and pharmaceutical industry scientists as a molecular tar...

Antidepressants and related psychiatric drugs are the most important prescription drugs worldwide, accounting for a market volume of 20 billion US$ per year. This handbook provides a complete and detailed overview of all currently available psychiatric drugs, covering more than 250 different compounds. Particular features include: the most importan...

Summary of drug classesDrugs in development

We investigated the function and expression of voltage-gated Na(+) channels (VGSC) in the uteri of nonpregnant rats using organ bath techniques, intracellular [Ca(2+)] fluorescence measurements, and RT-PCR. In longitudinally arranged whole-tissue uterine strips, veratridine, a VGSC activator, caused the rapid appearance of phasic contractions of ir...

The article contains sections titled:

Amino acid derived 3-pyrrolines can be readily prepared in a single step in enantiomerically pure form by cycloalkylation of the corresponding amino esters with (Z)-1,4-dichloro-2-butene. Enantiopure azabicyclo[3.3.0]octenones can be then easily obtained through an unprecedented Pauson-Khand reaction followed by ­diastereomer separation.

Modulation of constitutive activity by the recombinant wild-type human 5-HT6 receptor was investigated with a series of 5-HT6 receptor ligands by monitoring the cAMP signalling pathway. The impact of the mutation S267K near the B(261)BXXB(265) CIII-loop motif was analyzed on the magnitude of constitutive receptor activity as previously conflicting...

Two novel selective 5‐HT6 receptor ligands E‐6801 (6‐chloro‐ N ‐(3‐(2‐(dimethylamino)ethyl)‐1 H ‐indol‐5‐yl)imidazo[2,1‐ b ]thiazole‐5‐sulfonamide) and E‐6837 (5‐chloro‐ N ‐(3‐(2‐(dimethylamino)ethyl)‐1 H ‐indol‐5‐yl)naphthalene‐2‐sulfonamide) were investigated and compared to the putative 5‐HT6 receptor antagonists SB‐271046 (5‐chloro‐ N ‐(4‐metho...

E‐6837 is a novel, selective and high‐affinity 5‐HT 6 receptor ligand (p K i : 9.13) which in vitro demonstrates partial agonism at a presumably silent rat 5‐HT 6 receptor and full agonism at a constitutively active human 5‐HT 6 receptor by monitoring the cAMP signaling pathway. The effects of chronic treatment with E‐6837 were determined in diet‐i...

Voltage-gated Na+ channels are composed of one alpha subunit and one or more auxiliary beta subunits. A reverse transcription-polymerase chain reaction assay was used to analyse the expression of the nine known alpha subunits (Na(v)1.1-Na(v)1.9) in 20 different human tissues. The mRNA expression of the currently known beta subunits (beta1, beta2, b...

Although the 5-hydroxytryptamine(6) (5-HT(6)) receptor was discovered only recently, its almost exclusive distribution in the brain makes it a promising, novel, target for central nervous system (CNS)-mediated diseases such as Alzheimer's disease (cognitive function), schizophrenia, anxiety and obesity. In the past few years a significant research...

Based on a medicinal-chemistry-guided approach, three novel series of druglike cycloalkyl-annelated pyrazoles were synthesized and display high affinity (pKi>8) for the sigma1 receptor. Structure-affinity relationships were established, and the different scaffolds were optimized with respect to sigma1 binding and selectivity versus the sigma2 recep...

History of NSAIDsIsoforms of CyclooxygenaseClassification of NSAIDs According to their Chemical StructureThe Development of COX-2 Selective Inhibitors Classification According to COX Isoenzyme SelectivityClassification According to Drug-Protein InteractionsChemical Classification of Selective COX-2 InhibitorsDiaryl- and Aryl-Heteroaryl Ether and Th...

IntroductionThe Search for Opioids with Reduced Side-Effects

COX-1 and COX-2 Inhibitors in Clinical Use DiflunisalEthenzamideEtodolacEtofenamateEtoricoxibFenbufenFenoprofenFeprazoneFlobufenFlufenamic AcidFlurbiprofenIbuprofenIndomethacinIsoxicamKetoprofenKetorolacLonazolacLornoxicamMeclofenamic AcidMefenamic AcidMeloxicamMetamizol (Dipyrone)MofebutazoneNabumetone DiflunisalEthenzamideEtodolacEtofenamateEtori...

IntroductionGabapentiPregabalin

Asymmetric hydrogenation of (Z)-2-benzoylamino-3-(3,4-dimethoxyphenyl)-methyl acrylate with [Rh((S,S)-DIPAMP)(MeOH)2]BF4 was investigated. Low temperature NMR measurements prove the recently published X-ray structure of [Rh((S,S)-DIPAMP)((Z)-2-benzoylamino-3-(3,4-dimethoxyphenyl)-methyl acrylate)]BF4 to be the major substrate complex. The asymmetri...

Based on a medicinal chemistry guided hypothetical pharmacophore model, novel series of indolyl sulfonamides have been designed and prepared as selective and high-affinity serotonin 5-HT(6) receptor ligands. Furthermore, based on a screening approach of a discovery library, a series of benzoxazinepiperidinyl sulfonamides were identified as selectiv...

Screening of our internal chemical collection against the neuropeptide Y5 (NPY Y5) receptor allowed the identification of a benzoxazine derivative 5f as a hit that showed moderate affinity (IC(50) = 300 nM). With the aim of improving the in vitro potency, a series of 2-benzoxazinone derivatives have been synthesized and tested for NPY Y5 activity....

Fünf Katalysator-Substrat-Komplexe des Typs [Rh(chiraler Ligand)(β-Dehydroaminosäurederivat)]BF4 wurden erstmals röntgenstrukturanalytisch charakterisiert (siehe Beispiel). Tieftemperatur-NMR-Spektren zufolge handelt es sich bei drei Verbindungen um die „Major“-Substratkomplexe, die im Unterschied zu den klassischen Beispielen mit α-Dehydroaminosäu...

Five catalyst–substrate complexes of the type [Rh(chiral ligand)(β-dehydroamino acid derivative)]BF4 were characterized for the first time by X-ray analysis (see example). Low-temperature NMR spectroscopy proved that three of these complexes are “major” substrate complexes, which lead to the main product in asymmetric hydrogenation, contrary to the...

The invention relates to substituted (1H)-quinoxalin-2-one compounds, methods for production thereof, medicaments containing said compounds and the use of said compounds for the production of medicaments. The invention further relates to substituted 4-aryl- and 4-heteroarylcyclohexane compounds and methods for production thereof.